Preparation of (R)-(+)-N-[3-[5-[(4-Fluorophenyl)methyl]-2-thienyl]-1-methyl-2-propynyl]-N-hydroxyurea (ABT-761), a second-generation 5-lipoxygenase inhibitor.

Brooks, Clint D. W.; Stewart, Andrew O.; Basha, Anwer; Bhatia, Pramila; Ratajczyk, James D.; Martin, Jerry R.; Craig, Robert G.; Kolasa, Teodozyj; Bouska, Jennifer B.; Lanni, Carmine; Harris, Richard R.; Malo, Peter E.; Carter, George W.; Bell, Randy L.

doi:10.1021/jm00024a004

Cited by 44 publications

(15 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5-HETE or LTB 4 , as well as metabolites of cyclooxygenase, 12-, and 15-lipoxygenase. 49 Analysis can be performed by HPLC, enzyme immunoassay, or radioimmunoassay; kits for the latter two methods are commercially available.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of 5-lipoxygenase translocation inhibitors from acylnitroso hetero-Diels–Alder cycloadducts

et al. 2011

View full text Add to dashboard Cite

Acylnitroso cycloadducts have proven to be valuable intermediates in the syntheses of a plethora of biologically active molecules. Recently, organometallic reagents were shown to open bicyclic acylnitroso cycloadducts and, more interestingly, the prospect of highly regioselective openings was raised. This transformation was employed in the synthesis of a compound with excellent inhibitory activity against 5-lipoxygenase ((±)-4a, IC50 51 nM), an important mediator of inflammation intimately involved in a number of disease states including asthma and cancer. Optimization of the copper-mediated organometallic ring opening reaction was accomplished allowing the further exploration of the biological activity. Synthesis of a number of derivatives with varying affinity for metal binding as well as pendant groups in a range of sizes was accomplished. Analogues were tested in a whole cell assay which revealed a subset of the compounds to be inhibitors of enzyme translocation, a mode of action not previously known and, potentially, extremely important for better understanding of the enzyme and inhibitor development. Additionally, the lead compound was tested in vivo in an established colon cancer model and showed very encouraging anti-tumorogenic properties.

show abstract

Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of 5-lipoxygenase translocation inhibitors from acylnitroso hetero-Diels–Alder cycloadducts

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Despite its effectiveness, zileuton is not the first choice therapy due to its side effect such as nausea and idiosyncratic effects on the liver [ 93 ]. Further development of this class of inhibitors led to the identification of atreleuton, which inhibits LTB4 and cys-LTE4 production and has a potency that is about 5-fold enhanced in comparison to zileuton [ 94 ]. Atreleuton, which has entered clinical trials for atherosclerosis and cardiovascular diseases, is one of the leading 5-LO inhibitors in clinical development [ 95 ].…”

Section: Lipoxygenase Inhibitorsmentioning

confidence: 99%

Inflammation, Cancer and Oxidative Lipoxygenase Activity are Intimately Linked

Wisastra

Dekker

2014

Cancers

143

View full text Add to dashboard Cite

Cancer and inflammation are intimately linked due to specific oxidative processes in the tumor microenvironment. Lipoxygenases are a versatile class of oxidative enzymes involved in arachidonic acid metabolism. An increasing number of arachidonic acid metabolites is being discovered and apart from their classically recognized pro-inflammatory effects, anti-inflammatory effects are also being described in recent years. Interestingly, these lipid mediators are involved in activation of pro-inflammatory signal transduction pathways such as the nuclear factor κB (NF-κB) pathway, which illustrates the intimate link between lipid signaling and transcription factor activation. The identification of the role of arachidonic acid metabolites in several inflammatory diseases led to a significant drug discovery effort around arachidonic acid metabolizing enzymes. However, to date success in this area has been limited. This might be attributed to the lack of selectivity of the developed inhibitors and to a lack of detailed understanding of the functional roles of arachidonic acid metabolites in inflammatory responses and cancer. This calls for a more detailed investigation of the activity of arachidonic acid metabolizing enzymes and development of more selective inhibitors.

show abstract

“…were synthesized at Abbott Laboratories [6,7]. Other reagents were purchased from Sigma Chemical Company, St. Louis, MO, USA.…”

Section: Abt-491 Andmentioning

confidence: 99%

ABT-491, a highly potent and selective PAF antagonist, inhibits nasal vascular permeability associated with experimental allergic rhinitis in Brown Norway rats

Albert

Tapang

Morgan

et al. 1997

Inflammation Research

View full text Add to dashboard Cite

Preparation of (R)-(+)-N-[3-[5-[(4-Fluorophenyl)methyl]-2-thienyl]-1-methyl-2-propynyl]-N-hydroxyurea (ABT-761), a second-generation 5-lipoxygenase inhibitor.

Cited by 44 publications

References 5 publications

Synthesis and evaluation of 5-lipoxygenase translocation inhibitors from acylnitroso hetero-Diels–Alder cycloadducts

Synthesis and evaluation of 5-lipoxygenase translocation inhibitors from acylnitroso hetero-Diels–Alder cycloadducts

Inflammation, Cancer and Oxidative Lipoxygenase Activity are Intimately Linked

ABT-491, a highly potent and selective PAF antagonist, inhibits nasal vascular permeability associated with experimental allergic rhinitis in Brown Norway rats

Contact Info

Product

Resources

About